The luteinizing hormone-releasing hormone, LHRH, controls the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH). LHRH antagonists are compounds capable of blocking the secretion of FSH and LH. They are generally nona- and decapeptides (but may be shorter or longer) comprising part of or the entire structure of LHRH in which one or several amino acids have been exchanged for other natural amino acids and/or amino acids not found in nature.
Synthetic LHRH antagonists may be used for contraception and in the treatment of benign hyperplasia of the prostate gland, hormonal-dependent tumors of the breast and ovaries, dysmenorrhea, endometriosis, and other conditions. These synthetic LHRH antagonists have the general formulaAc-D-2Nal-D-4ClPhe-D-3Pal-Ser-X-NH2,wherein X is from 5 to 6 natural and/or synthetic amino acid residues. More particularly they have the aforementioned general formula wherein X is AA1-AA2-Leu-AA3-Pro-D-Ala, in particular wherein AA1 is a natural or synthetic amino acid and AA2 is a natural or synthetic amino acid or zero, AA3 is a natural or synthetic amino acid.
While there are a number of synthetic methods for preparing LHRH analogs known in the art, there is a need for improvement since the total yield of LHRH analogs obtained from known processes is not high and the products, in addition, may require extensive purification. Moreover, the methods for the synthesis of LHRH analogs known in the art are quite costly.
A synthesis strategy disclosed in U.S. Pat. No. 5,710,246 for making decapeptide or nonapeptide LHRH antagonists comprises the coupling of an intermediate tripeptide representing amino residues 1 to 3 (counting starts at the amino terminal of the peptide) with a heptapeptide or a hexapeptide, respectively representing amino acid residues 4-10 and 4-9, respectively. The intermediate tripeptide disclosed in U.S. 5,710,246 A is an ester, Boc-D-2Nal-D-4ClPhe-D-3Pal-O-Me or the corresponding benzyl or allyl ester.